Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12622000007730
Ethics application status
Approved
Date submitted
23/09/2021
Date registered
11/01/2022
Date last updated
11/01/2022
Date data sharing statement initially provided
11/01/2022
Date results information initially provided
11/01/2022
Type of registration
Retrospectively registered

Titles & IDs
Public title
The Effect of Surgical Humidification in Colorectal Cancer Surgery: a Randomised Controlled Trial
Scientific title
The Effect of Surgical Humidification on Local and Systemic inflammation and Peritoneal Trauma in Colorectal Cancer Surgery: a Randomised Controlled Trial
Secondary ID [1] 305378 0
None
Universal Trial Number (UTN)
U1111-1269-7067
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
colorectal cancer 323729 0
Condition category
Condition code
Cancer 321257 321257 0 0
Bowel - Back passage (rectum) or large bowel (colon)
Surgery 321258 321258 0 0
Surgical techniques

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Delivery of warmed, humidified CO2 to the peritoneal cavity during laparoscopic and open abdominal colorectal cancer surgery.
Participants in the study group will receive warmed (37 degrees Celsius), humidified (98%) CO2 via insufflation in the minimally invasive group or wound insufflation in the open group.
The HumiGardTM humidification system (MR860; Fisher and Paykel Health Care, Auckland, New Zealand) has been independently tested to confirm the effectiveness of gas humidification.
Anticipated duration of surgery for any group is between 2 to 4 hours.
For both laparoscopic surgery groups, pneumoperitoneum will be established after insertion of a 12mm port by open method. Further 10mm and 5mm ports will be inserted according to the type of laparoscopic procedure. The laparoscopic control group will receive non humidified unwarmed CO2 delivered by a standard insufflator. For the study laparoscopic group the insufflation tubing will include the humidification system consists of a bacterial filter and a humidification chamber filled with 180 mL sterile water, attached to a humidifier controller that includes an integrated temperature and flow sensor. The outlet of the humidification chamber is connected to a thermally insulated 2.5m long heated insufflation tube that maintains temperature and humidity of the gas to its outlet.
In the open group dry CO2 is delivered via a 6.35mm polyvinylchloride tube to the open surgery humidification system (F&P HumiGard, Fisher & Paykel Healthcare Ltd, Auckland, New Zealand). This is attached to flexible tubing and positioned inside the open abdominal wound cavity in the right upper quadrant, a depth of approximately 4 cm from the skin. Insufflation of warmed, humidified CO2 will be continued from the time the laparotomy incision is made until just before abdominal wall closure. The control open group will not receive any insufflation.
Adherence to protocol, the pressure, flow rate and total volume of CO2 delivered will be recorded by an observer in the operating room for both groups.
Intervention code [1] 321789 0
Treatment: Devices
Comparator / control treatment
The control group will have surgery performed with traditional cold, dry CO2 delivered at 20 to 22 degrees Celsius in the laparoscopic group and no wound insufflation in the open group.

Both groups use the same laparoscopic ports , the only difference is the tube that delivers the gas - it doesn't take any more or less time to connect or setup.
the laparoscopic humidifier is a standard piece of equipment that has been in routine use for over 15 years. no special training required for this trial


Control group
Active

Outcomes
Primary outcome [1] 329041 0
Assessment of peritoneal tissue damage, as measured by peritoneal morphological changes.
Timepoint [1] 329041 0
Peritoneal fluid and peritoneal biopsies will be taken at the start of the operation, then 2-hourly intra-operatively.
Secondary outcome [1] 401249 0
Change in marker of systemic inflammation: Interleukin-6 (Il-6)
Timepoint [1] 401249 0
Blood samples will be collected pre operatively, at 2 hours and 4 hours post induction (intra operative), and post-operative at 24 and 72 hours.
Secondary outcome [2] 401250 0
Peri-operative body temperature as recorded by oesophageal temperature probe or infrared temperature monitor
Timepoint [2] 401250 0
Body temperature will be recorded preoperatively, intra-operatively at 15 minute intervals, at completion of procedure while in the operating room and in recovery (or ICU if patient transported directly) half hourly for two hours post operatively by oesophageal temperature probe or infrared temperature monitor.
Secondary outcome [3] 401251 0
Length of stay (LOS) determined by identifying postoperative day of discharge from medical record review and calculating the number of days since surgery.
Timepoint [3] 401251 0
Post-operative day of discharge
Secondary outcome [4] 401950 0
Change in marker of systemic inflammation: Interleukin-8 (Il-8)
Timepoint [4] 401950 0
Blood samples will be collected pre operatively, at 2 hours and 4 hours post induction (intra operative), and post-operative at 24 and 72 hours.
Secondary outcome [5] 401951 0
Change in marker of systemic inflammation: Interleukin-10 (Il-10)
Timepoint [5] 401951 0
Blood samples will be collected pre operatively, at 2 hours and 4 hours post induction (intra operative), and post-operative at 24 and 72 hours.
Secondary outcome [6] 401952 0
Change in marker of systemic inflammation: Tumor necrosis factor alpha (TNF-a)
Timepoint [6] 401952 0
Blood samples will be collected pre operatively, at 2 hours and 4 hours post induction (intra operative), and post-operative at 24 and 72 hours.
Secondary outcome [7] 401953 0
Change in marker of systemic inflammation: C-reactive protein (CRP)
Timepoint [7] 401953 0
Blood samples will be collected pre operatively, at 2 hours and 4 hours post induction (intra operative), and post-operative at 24 and 72 hours.
Secondary outcome [8] 401954 0
Change in marker of systemic inflammation: Vascular Endothelial Growth Factor VEGF-A,
Timepoint [8] 401954 0
Blood samples will be collected pre operatively, at 2 hours and 4 hours post induction (intra operative), and post-operative at 24 and 72 hours.
Secondary outcome [9] 401955 0
Change in marker of systemic inflammation: Cocly-oxygenase -2 (COX-2)
Timepoint [9] 401955 0
Blood samples will be collected pre operatively, at 2 hours and 4 hours post induction (intra operative), and post-operative at 24 and 72 hours.
Secondary outcome [10] 401956 0
Change in Circulating Tumor DNA (ctDNA)
Timepoint [10] 401956 0
Blood samples will be collected pre operatively, at 2 hours and 4 hours post induction (intra operative), and post-operative at 24 and 72 hours.
Secondary outcome [11] 401962 0
Change in marker of systemic inflammation: Prostaglandin E2 (PGE2)
Timepoint [11] 401962 0
Blood samples will be collected pre operatively, at 2 hours and 4 hours post induction (intra operative), and post-operative at 24 and 72 hours.

Eligibility
Key inclusion criteria
All patients undergoing elective colorectal cancer surgery for any indication
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
• Patients under age 18
• Patients with known intra-abdominal sepsis
Pre-operative steroid dependence
Patients who are pregnant
Prior diagnosis of Crohns or ulcerative colitis
Inability to consent due to cognitive or language barrier
Preoperative blood transfusion

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Randomisation will be performed separately for each site and by surgical approach (laparoscopic/open). Allocation to study or control group will occur intra-operatively by envelope.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Randomisation will be blocked to achieve even numbers in each group of warmed, humidified and cold dry. Using computer based random number generator (www.random.org) will be used to randomize patients.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
The following continuous valued markers of local inflammation will be considered:
- IL6
- IL 8
- IL 10
- TNF-a

For each of the above continuous valued markers of local inflammation, a linear regression model will be constructed to test for a difference in the mean value of that marker of inflammation, between patients treated with humidification, and patients treated without humidification. Surgical technique will be controlled for in the model if necessary. The independent variables will be the presence/absence of humidification, and surgical technique (if necessary). The marker of inflammation of interest will be the dependent variable. The difference in mean value of the marker between patients treated with humidification, and patients treated without humidification, together with its 95% CI will be reported. The assumption of normally distributed residuals will be tested for, and a suitable monotonic transformation (e.g. log transformation) will be considered if necessary.
The following Boolean valued markers of local inflammation will be considered
• COX-2
• VEGF-A

For each of the above markers of local inflammation, binary logistic regression will be used to test for a difference in the proportion of patients with that marker of inflammation, between patients treated with humidification, and patients treated without humidification. Surgical technique will be controlled for in the model if necessary. The independent variables will be the presence/absence of humidification, and surgical technique (if necessary). The marker of inflammation of interest will be the dependent variable. The odds ratio for humidification together with its 95% CI will be reported.

The following measures of peritoneal tissue damage will be considered
• loss of microvilli
• mesothelial cell bulging and retraction
• widening of intercellular junctions
• exposed basal lamina

The percentage of remaining normal microvilli will be calculated.
Each of the above measures of peritoneal tissue damage is ordinal valued and may take values in the range 1 to 3. For each measure of peritoneal tissue damage, statistical analysis will proceed as follows. An ordinal logistic regression model will be constructed with the measure of peritoneal tissue damage as the dependent variable and the presence/absence of humidification, and surgical technique (if necessary to control for confounding) as the independent variables. The odds ratio of humidification corresponding to a one level change in the measure of peritoneal tissue damage, together with its 95% CI will be reported.
For each of the continuous valued measures, a linear regression model will be constructed with humidification and surgical technique (if necessary to control for confounding) as the independent variables and the continuous valued measure of interest as the independent variables. The difference in mean value of each continuous valued measure between levels of humidification status will be reported together with its 95% CI. For each of the temperature measures, the method will be repeated for temperature measured at both 1 hour and 4 hours after the start of surgery.

In addition, a mixed effects model will be constructed using temperature (measured at 15 minute intervals during surgery) as the dependent variable, time since start of surgery, surgical technique (if necessary to control for confounding) and humidification as fixed effects, and patient as the random effect. By including a term for the interaction between time and humidification, differences in change in temperature over time as a function of humidification will be tested for.

In order to test for a difference between humidification and presence of ctDNA (Boolean valued), a binary logistic regression model will be built, analogous to that for the first primary objective. Presence of ctDNA will be the dependent variable, and humidification and surgical technique (if necessary to control for confounding) will be the independent variables. Perioperative use of steroids and presence of metastatic disease will be considered as additional potential confounders and included in the model if necessary. The odds ratio corresponding to humidification and its 95% CI will be reported.

In order to test for a difference between surgical technique and presence of ctDNA (Boolean valued), a binary logistic regression model will be built, analogous to that for the previous secondary objective. As previously, presence of ctDNA will be the dependent variable. However in this case, the prime independent variable of interest will be surgical technique, and humidification, perioperative use of steroids and presence of metastatic disease will be included in the model to control for confounding if necessary.

A simple linear regression model will be constructed with time from end of surgery until transfer to recovery room as the independent variable, and temperature change between end of surgery and transfer to recovery room as the dependent variable. The slope of the regression line of best fit and its 95% CI will be reported.

Power Calculation:

For a comparison of proportions between arms in a two arm trial, a sample size of 120 per arm is sufficient to detect a fairly small effect size 0f 0.36 with power of 0.8. If the overall proportion across both arms is in the vicinity of 0.5, this is enough to detect an approximate 18% difference in proportions between the arms.

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Participant recruitment difficulties
Date of first participant enrolment
Anticipated
Actual
20/04/2016
Date of last participant enrolment
Anticipated
Actual
29/04/2019
Date of last data collection
Anticipated
1/05/2022
Actual
6/01/2021
Sample size
Target
240
Accrual to date
Final
66
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 309747 0
Commercial sector/Industry
Name [1] 309747 0
Fisher & Paykel Healthcare Limited
Country [1] 309747 0
New Zealand
Primary sponsor type
Hospital
Name
Epworth Hospital
Address
89 Bridge Road
Richmond VIC 3121
Country
Australia
Secondary sponsor category [1] 310768 0
Hospital
Name [1] 310768 0
Peter Maccallum Cancer Centre
Address [1] 310768 0
300 Grattan Street
Melbourne
VIC 3000
Country [1] 310768 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309503 0
Peter MacCallum Cancer Centre HREC
Ethics committee address [1] 309503 0
305 Grattan Street
Melbourne VIC 3000
Australia
Ethics committee country [1] 309503 0
Australia
Date submitted for ethics approval [1] 309503 0
31/05/2016
Approval date [1] 309503 0
15/03/2019
Ethics approval number [1] 309503 0
LARF/52753/PMCC-2019
Ethics committee name [2] 309511 0
Epworth HealthCare Ethics Committee
Ethics committee address [2] 309511 0
Mailbox #4, 89 Bridge Road, Richmond, VIC 3121
Ethics committee country [2] 309511 0
Australia
Date submitted for ethics approval [2] 309511 0
16/11/2015
Approval date [2] 309511 0
02/12/2015
Ethics approval number [2] 309511 0
HREC 677-15

Summary
Brief summary
Pre-clinical studies indicate that insufflation using dry-cold carbon dioxide (DC-CO2) leads to peritoneal cellular damage, inflammation and hypothermia compared humidified warm-CO2 (HW-CO2). These parameters were explored in patients undergoing surgery for colorectal cancer.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 114382 0
A/Prof Craig Lynch
Address 114382 0
Cancer Specialists
Level 1, 84 Bridge Road
Richmond
VIC 3121
Country 114382 0
Australia
Phone 114382 0
+61 394216425
Fax 114382 0
Email 114382 0
craig@craiglynch.com.au
Contact person for public queries
Name 114383 0
A/Prof Craig Lynch
Address 114383 0
Cancer Specialists
Level 1, 84 Bridge Road
Richmond
VIC 3121
Country 114383 0
Australia
Phone 114383 0
+61 394216425
Fax 114383 0
Email 114383 0
craig@craiglynch.com.au
Contact person for scientific queries
Name 114384 0
A/Prof Craig Lynch
Address 114384 0
Cancer Specialists
Level 1, 84 Bridge Road
Richmond
VIC 3121
Country 114384 0
Australia
Phone 114384 0
+61 394216425
Fax 114384 0
Email 114384 0
craig@craiglynch.com.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
Not released by Peter Mac


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
13329Ethical approval    382831-(Uploaded-23-09-2021-14-54-13)-Study-related document.pdf
13330Statistical analysis plan    see study protocol
13331Study protocol    382831-(Uploaded-23-09-2021-14-48-42)-Study-related document.docx



Results publications and other study-related documents

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